Abstract Acute Kidney Injury (AKI) is characterized as an abrupt decrease in kidney function. AKI is one of the most serious and common health complications, occurring in up to 20% of all hospitalized patients and over 45% of patients in a critical care setting. AKI is particularly prevalent among populations already susceptible such as renal transplant recipients, patients with cardiac arrest, or septic shock. As the kidney is a highly vascularized organ, the complex vasculature is extremely sensitive to damage during AKI, however, the role of the microvasculature during ischemic injury is vastly understudied. The long-term goal of this study is to determine whether subtle developmental defects of the microvasculature lead to increased susceptibility to ischemic injury. Our preliminary data using conditional mouse deletion of Vascular Endothelial Growth Factor Receptor 2 (Flk1, expressed on endothelium) in the Foxd1 positive stromal mesenchyme demonstrates a critical role of the stromally derived endothelial cells in patterning the renal vasculature both developmentally and in the adult. Vessels appear dilated in mutants compared to controls. To test whether these endothelial cells play a critical role during ischemic injury we utilized transgenic mice where the stromally derived endothelial cells expressed red fluorescent protein and subjected these mice to ischemia reperfusion injury (IRI). We found that the stromally derived endothelium were particularly responsive 7 days post IRI. When we performed IRI or drug induced AKI with the conditional knockout mice we found that these animals had more severe renal injury including a reduction in perfusion, increase in hypoxia and severe tubular damage. Taken together we hypothesize that stromally derived endothelium are critical mediators for kidney injury.